Unraveling signaling mechanisms regulating cluster‐based metastasis
Abstract
There is mounting evidence that tumor cells can migrate and metastasize as cell clusters. The presence of circulating tumor cell clusters is associated with early relapse and death in many cancer types. Experimentally, clustering of tumor cells greatly increases colonizing potential, but the molecular mechanisms explaining this phenomenon are largely unknown. We performed time‐lapse imaging and genome wide transcription studies in mouse and human breast tumor organoids. This revealed that clustering of tumor cells rapidly induces expression of multiple EGFR pathway genes and increased auto‐phosphorylation of EGFR. Interestingly, pEGFR colocalized with multiple EGFR ligands at cell‐cell contacts, suggesting that clusters' EGFR activation may be due to increased ligand binding. Consistent with this hypothesis, RNAi knockdowns of multiple individual ligands reduced tumor organoid growth by 40 to 95% of control. Downstream of receptor activation, expression of EGFR effector pERK was increased in clusters. The most significantly cluster‐upregulated transcription factor was the ERK‐activated oncogene Fra1. Fra1 knockdown reduced growth as did ERK inhibition. Using patient breast cancer samples, including primary and metastatic tumors, we found that Fra1 expression was highly upregulated in human tumor cell clusters, supporting the human disease relevance of this pathway. Taken together, our studies show that tumor cell clusters activate EGFR‐ERK‐Fra1 growth signaling at cell‐cell contacts. We propose that disrupting this pathway could reduce metastasis and extend survival in cancer patients.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2019
- Source ID
- 10.1096/fasebj.2019.33.1_supplement.82.1
Entities
People
- Aaron Thomas
- Ami Yamamoto
- Breanna Moore
- Emma D. Wrenn
- Erin Greenwood
- Kevin M Cheung
- Margaux Mcbirney
Organizations
- Burroughs Wellcome Fund
- Fred Hutchinson Cancer Center
- Susan G. Komen for the Cure
- The Breast Cancer Research Foundation
- United States Department of Defense
- V Foundation for Cancer Research